title: Cyclic enkephalins with a diversely substituted guanidine bridge or a thiourea bridge: synthesis, biological and structural evaluations.
abstract: Two series of 22 and 15 atom cyclic enkephalins incorporating a diversely substituted guanidine bridge have been prepared to assess the potential effect of the bridge substitutions on their opioid activity profile. The most notable results were obtained with the shortest cyclic analogues, which showed a significant variation of their binding affinity toward μ and δ opioid receptors in relation to bridge substitution. NMR studies were performed to rationalize these data. Some small analogues were found to exist as at least one major and one minor stable forms, which could be separated by chromatography. In particular, the compounds 13 and 14 with a cyclic substituent were separated in three isomers and the basis of this multiplicity was explored by 2D NMR spectroscopy. All compounds were agonists with slight selectivity for the μ opioid receptor. Compounds 7a (thiourea bridge) and 10a (N-Me-guanidine bridge) showed nanomolar affinity toward μ receptor, the latter being the more selective for this receptor (40-fold).
authors.affiliation: Institut des Biomolécules Max Mousseron, CNRS UMR 5247, Université Montpellier 1, Université Montpellier 2, Faculté de Pharmacie, 15 Avenue Charles Flahault, 34093 Montpellier cedex 05, France.
authors.forename: Youness
authors.initials: Y
authors.lastname: Touati-Jallabe
authors.affiliation: Biological Research Center, Institute of Biochemistry, POB 521, H-6702 Szeged, Hungary.
authors.forename: Engin
authors.initials: E
authors.lastname: Bojnik
authors.affiliation: Laboratoire de Chimie Physique Macromoléculaire, CNRS UMR 7568, Université de Lorraine, 1 rue Grandville, 54001 Nancy Cedex, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Legrand
authors.affiliation: Institut des Biomolécules Max Mousseron, CNRS UMR 5247, Université Montpellier 1, Université Montpellier 2, Faculté de Pharmacie, 15 Avenue Charles Flahault, 34093 Montpellier cedex 05, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Mauchauffée
authors.affiliation: Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Nga N
authors.initials: NN
authors.lastname: Chung
authors.affiliation: Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec H2W 1R7, Canada.|Department of Pharmacology, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
authors.affiliation: Biological Research Center, Institute of Biochemistry, POB 521, H-6702 Szeged, Hungary.
authors.forename: Sandor
authors.initials: S
authors.lastname: Benyhe
authors.affiliation: Laboratoire de Chimie Physique Macromoléculaire, CNRS UMR 7568, Université de Lorraine, 1 rue Grandville, 54001 Nancy Cedex, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Averlant-Petit
authors.affiliation: Institut des Biomolécules Max Mousseron, CNRS UMR 5247, Université Montpellier 1, Université Montpellier 2, Faculté de Pharmacie, 15 Avenue Charles Flahault, 34093 Montpellier cedex 05, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Martinez
authors.affiliation: Institut des Biomolécules Max Mousseron, CNRS UMR 5247, Université Montpellier 1, Université Montpellier 2, Faculté de Pharmacie, 15 Avenue Charles Flahault, 34093 Montpellier cedex 05, France.
authors.forename: Jean-Franćois
authors.initials: JF
authors.lastname: Hernandez
mesh_terms: D000818:Animals; D004745:Enkephalins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019791:Guanidine; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013890:Thiourea
chemical_list: D004745:Enkephalins; D010456:Peptides, Cyclic; D017450:Receptors, Opioid, mu; D013890:Thiourea; D019791:Guanidine